Corticostriatal functional connectivity predicts transition to chronic back pain

Abstract

The mechanism of brain reorganization in pain chronification is unknown. In a longitudinal brain imaging study, subacute back pain (SBP) patients were followed over the course of 1 year. When pain persisted (SBPp, in contrast to recovering SBP and healthy controls), brain gray matter density decreased. Initially greater functional connectivity of nucleus accumbens with prefrontal cortex predicted pain persistence, implying that corticostriatal circuitry is causally involved in the transition from acute to chronic pain.

Fig. 1. Changes in global and regional gray matter density over 1 year

(a) Recovering SBP patients, SBPr (in contrast to persisting, SBPp) exhibited decreases in pain intensity with time. Horizontal bars represent range of times for each visit in each group (SBPp, black; SBPr, grey; healthy controls,white), red lines are the mean. Pain duration at visit 1 was not different between the groups (SBPp: mean=14.08 weeks, S.E.M.=0.97; SBPr: mean=12.36 weeks, S.E.M. = 1.04; unpaired t–test: t=1.68, p=0.16). (b) Gray matter volume only decreased in time in SBPp (Group*Visit F_{6, 147}=3.23. p<0.01). (c) Whole–brain voxelwise repeated measures ANOVA for gray matter density changes in time for SBPp. Regions (red–yellow) that significantly changed in gray matter density included: bilateral NAc, insula, and left S1/M1 (Supplementary Table 3). (d) Region of interest (ROI) analyses for right NAc and right insula showed decreased gray matter only in SBPp. The study was approved by Institutional Review Board of Northwestern University. [+p<0.05, ++p<0.01, within group comparison to visit 1; ** p<0.01 comparison to Healthy at corresponding time]. Error bars are S.E.M.

Fig. 2. Functional connectivity of NAc and insula

(a) Whole–brain voxelwise contrast of NAc (green) functional connectivity (links) between SBPp and SBPr. SBPp showed (red–yellow) significantly stronger positive connections between NAc and mPFC at both visits. (b) Average total number of voxels exhibiting positive (z(r) >0.25) and negative (z(r) < −0.25) links to NAc. Positive functional connections were larger in SBPp at both visits. (Group F_{1, 34}=8.80. p<0.01). (c) In SBPp, the number of NAc positive links correlated to affective pain (computed from the affective descriptors of McGill pain questionnaire at the day of the scan) at both visits. (d) Whole–brain voxelwise contrast of insula (green) functional connectivity. SBPp showed decreased negative correlations between insula and dLPFC/PCC in time (Group*Visit F_1,34=4.04. p<0.05). (e) Positive and negative links to insula. SBPp showed decreased negative links at visit 4. (f) In SBPp and at visit 4, number of negative links to insula was related to insula gray matter density (left), and to pain intensity (right). [*p<0.05 in comparison to Healthy], [++p<0.01, within group comparison]. Error bars are S.E.M.

Fig. 3. mPFC–NAc functional connectivity predicts pain chronification

(a) Location and coordinates of the mPFC and NAc seeds used. (b) mPFC–NAc functional connectivity in SBPp was higher than in SBPr in separate fMRI scans. (c) Receiver–operator characteristic (ROC) curves and discrimination probabilities (D, area under ROC curve) for predicting pain persistence at visits 2, 3 and 4 using mPFC–NAc at visit 1’ (unbiased estimate). (d) In a separate validation group (n=13), mPFC–NAc strengths at visit 1 (inset), and ROC and D–values of visit 1 predicting persistence of pain at visit 4. [*p<0.05, **p<0.001] Error bars are S.E.M.